Combination pharmacotherapy: A mixture of small doses of naltrexone, fluoxetine, and a thyrotropin-releasing hormone analogue reduces alcohol intake in three strains of alcohol-preferring rats

It is common to treat some diseases with more than one medication simultane ously Since more than one neurotransmitter system is involved in alcohol-se eking behaviour, then a therapeutic approach that targets more than one sys tem should be more effective in reducing alcohol intake than one addressing a single system. To test this hypothesis, we compared the efficacy of low doses of individual drugs reported to reduce voluntary alcohol drinking to the efficacy of a mixture of these agents at the same low doses in reducing alcohol intake in three strains of alcohol-preferring rats (P, HAD, and Fa wn-Hooded). After establishment of a stable baseline for alcohol intake in a continuous access paradigm. each rat received separate single i.p. inject ions of relatively low doses of either naltrexone (2.0 mg/kg), fluoxetine ( 1.0 mg/kg), the thyrotropin-releasing hormone analogue TA-0910 (0.2 mg). a mixture of all three drugs, or the vehicle at 09:30. Each rat received all treatments, with an inter-injection washout period of at least 3 days. Alco hol and water intakes were measured at 6 and 24 h, and food intake was meas ured at 24 h, after the injection. Our results show that individual drugs d id not significantly affect food, water, or alcohol intake. However, the mi xture significantly reduced alcohol intake in all three strains, but had no effect on food intake. Similar results were obtained when the HAD rats rec eived an oral dose of the individual drugs or the mixture. When P rats were given an i.p. injection of the mixture for 10 consecutive days, there was a continued suppressing effect. These findings show that a combination trea tment designed to target simultaneously serotonergic, dopaminergic, and opi oidergic systems can reduce alcohol intake, even though the doses of the in dividual drugs in the mixture are relatively low and ineffective when given singly.